Intracellular signaling plays a crucial role in lymphocyte development and function. Although a large number of signaling molecules have identified, it remains to be elucidated how the activation of an individual signaling molecule contributes to various in vivo physiological phenomena such as control of antigen receptor gene rearrangement, repertoire selection, tolerance induction, peripheral lymphocyte activation and maintenance of immune memory. Since these questions can only be properly addressed in different in vivo systems, this project focuses on developing animal models using gene targeting and transgenic approaches, and then using various cellular, molecular and biochemical methods to analyze the impact of various altered signaling pathway on the development, function and pathology of lymphocytes in vivo. We are currently interested in understanding the regulatory functions of the protein tyrosine kinases such as Ctk, as well as the so called adaptor signaling molecules including Grb2 and c-cbl. For this reason, we have established several animal models in which these molecules are inactivated either in the germline or potentially at different stages of animal development. So far, Ctk-/-, c-cbl-/-, Grb2-/+ and Grb2floxed mice have been obtained in our laboratory. These model systems may allow us to study in detail intracellular signaling mechanisms involved in lymphocyte development and function in a more physiological situation.